Inhibitory Effect of Luteolin on Spike S1 Glycoprotein-Induced Inflammation in THP-1 Cells via the ER Stress-Inducing Calcium/CHOP/MAPK Pathway.

IF 4.3 3区医学 Q2 CHEMISTRY, MEDICINAL

Pharmaceuticals Pub Date : 2024-10-20 DOI:10.3390/ph17101402

Sonthaya Umsumarng, Sivamoke Dissook, Punnida Arjsri, Kamonwan Srisawad, Pilaiporn Thippraphan, Apiwat Sangphukieo, Patcharawadee Thongkumkoon, Pornngarm Dejkriengkraikul

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引用次数: 0

Abstract

Background/objectives: The global SARS-CoV-2 outbreak has escalated into a critical public health emergency, with the spike glycoprotein S1 subunit of SARS-CoV-2 (spike-S1) linked to inflammation in lung tissue and immune cells. Luteolin, a flavone with anti-inflammatory properties, shows promise, but research on its effectiveness against long-COVID-related inflammation and spike protein-induced responses remains limited. This study aims to elucidate the underlying mechanisms of inflammation in THP-1 cells induced by the spike-S1. Additionally, it seeks to assess the potential of luteolin in mitigating inflammatory responses induced by the spike-S1 in a THP-1 macrophage model.

Methods: The gene expression profiles of spike-S1 in THP-1 cells were analyzed by transcriptome sequencing. The inhibitory effect of luteolin on ER stress and inflammation in spike-S1-induced THP-1 cells was investigated using Western blotting, RT-PCR, and ELISA.

Results: The candidate genes (CAMK2A, SIGLEC7, PPARGC1B, SEC22B, USP28, IER2, and TIRAP) were upregulated in the spike-S1-induced THP-1 group compared to the control group. Among these, calcium/calmodulin-dependent protein kinase II alpha (CAMK2A) was identified as the most promising molecule in spike-S1-induced THP-1 cells. Our results indicate that the spike S1 significantly increased the expression of ER-stress markers at both gene and protein levels. Luteolin significantly reduced ER stress by decreasing the expression of ER-stress marker genes and ER-stress marker proteins (p < 0.01). Additionally, luteolin exhibited anti-inflammatory properties upon spike S1-induction in THP-1 cells by significantly suppressing IL-6, IL-8, and IL-1β cytokine secretion in a dose-dependent manner (p < 0.05). Furthermore, our results revealed that luteolin exhibited the downregulation of the MAPK pathway, as evidenced by modulating the phosphorylation of p-ERK1/2, p-JNK and p-p38 proteins (p < 0.05).

Conclusions: The results from this study elucidate the mechanisms by which the spike S1 induces inflammation in THP-1 cells and supports the use of naturally occurring bioactive compounds, like luteolin, against inflammation-related SARS-CoV-2 infection.

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木犀草素通过ER应激诱导钙/CHOP/MAPK通路抑制穗状S1糖蛋白诱导的THP-1细胞炎症反应

背景/目的全球 SARS-CoV-2 爆发已升级为严重的公共卫生紧急事件，SARS-CoV-2（spike-S1）的尖峰糖蛋白 S1 亚基与肺组织和免疫细胞的炎症有关。木犀草素是一种具有抗炎特性的黄酮类化合物，具有广阔的前景，但有关它对长期CoVID相关炎症和尖峰蛋白诱导反应的有效性的研究仍然有限。本研究旨在阐明尖峰蛋白-S1 诱导 THP-1 细胞炎症的基本机制。此外，本研究还试图评估叶黄素在 THP-1 巨噬细胞模型中减轻尖峰蛋白诱导的炎症反应的潜力：方法：通过转录组测序分析了穗状-S1 在 THP-1 细胞中的基因表达谱。方法：通过转录组测序分析了穗状-S1 在 THP-1 细胞中的基因表达谱，并使用 Western 印迹、RT-PCR 和 ELISA 研究了木犀草素对穗状-S1 诱导的 THP-1 细胞中 ER 应激和炎症的抑制作用：结果：与对照组相比，候选基因（CAMK2A、SIGLEC7、PPARGC1B、SEC22B、USP28、IER2 和 TIRAP）在尖峰-S1 诱导的 THP-1 组中上调。其中，钙/钙调蛋白依赖性蛋白激酶 II alpha（CAMK2A）被认为是尖峰-S1 诱导的 THP-1 细胞中最有潜力的分子。我们的研究结果表明，秒杀 S1 在基因和蛋白水平上都显著增加了 ER 应激标记物的表达。叶黄素通过降低ER应激标记基因和ER应激标记蛋白的表达，明显降低了ER应激（p < 0.01）。此外，在穗状 S1 诱导的 THP-1 细胞中，木犀草素具有抗炎特性，能以剂量依赖的方式显著抑制 IL-6、IL-8 和 IL-1β 细胞因子的分泌（p < 0.05）。此外，我们的研究结果表明，木犀草素具有下调 MAPK 通路的作用，这一点通过调节 p-ERK1/2、p-JNK 和 p-p38 蛋白的磷酸化得到了证明（p < 0.05）：本研究的结果阐明了尖峰 S1 在 THP-1 细胞中诱导炎症的机制，并支持使用天然生物活性化合物（如木犀草素）来对抗与炎症相关的 SARS-CoV-2 感染。

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来源期刊

Pharmaceuticals Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science

CiteScore

6.10

自引率

4.30%

发文量

1332

审稿时长

6 weeks

期刊介绍： Pharmaceuticals (ISSN 1424-8247) is an international scientific journal of medicinal chemistry and related drug sciences.Our aim is to publish updated reviews as well as research articles with comprehensive theoretical and experimental details. Short communications are also accepted; therefore, there is no restriction on the maximum length of the papers.